Association between Statins Types with Incidence of Liver Cancer: An Updated Meta-analysis

Background Previous studies have found a potential role for statins in liver cancer prevention. Objective This study aimed to explore the effect of different types of statins on the incidence of liver cancer. Methods Relevant articles were systematically retrieved from PubMed, EBSCO, Web of Science, and Cochrane Library databases from inception until July 2022 to explore the relationship between lipophilic statins or hydrophilic statins exposure and the incidence of liver cancer. The main outcome was the incidence of liver cancer. Results Eleven articles were included in this meta-analysis. The pooled results showed a reduced incidence of liver cancer in patients exposed to lipophilic statins (OR=0.54, p < 0.001) and hydrophilic statins (OR=0.56, p < 0.001) compared with the non-exposed cohort. Subgroup analysis showed that both exposures to lipophilic (Eastern countries: OR=0.51, p < 0.001; Western countries: OR=0.59, p < 0.001) and hydrophilic (Eastern countries: OR=0.51, p < 0.001; Western countries: OR=0.66, p=0.019) statins reduced the incidence of liver cancer in Eastern and Western countries, and the reduction was most significant in Eastern countries. Moreover, atorvastatin (OR=0.55, p < 0.001), simvastatin (OR=0.59, p < 0.001), lovastatin (OR=0.51, p < 0.001), pitavastatin (OR=0.36, p=0.008) and rosuvastatin (OR=0.60, p=0.027) could effectively reduce the incidence of liver cancer, unlike fluvastatin, cerivastatin and pravastatin. Conclusion Both lipophilic and hydrophilic statins contribute to the prevention of liver cancer. Moreover, the efficacy was influenced by the region and the specific type of statins used.


INTRODUCTION
Rationale 3 Describe the rationale for the review in the context of existing knowledge.P4 Objectives 4 Provide an explicit statement of the objective(s) or question(s) the review addresses.P4

METHODS
Eligibility criteria 5 Specify the inclusion and exclusion criteria for the review and how studies were grouped for the syntheses.P5 Information sources 6 Specify all databases, registers, websites, organisations, reference lists and other sources searched or consulted to identify studies.Specify the date when each source was last searched or consulted.

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Search strategy 7 Present the full search strategies for all databases, registers and websites, including any filters and limits used.P4 Selection process 8 Specify the methods used to decide whether a study met the inclusion criteria of the review, including how many reviewers screened each record and each report retrieved, whether they worked independently, and if applicable, details of automation tools used in the process.

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Data collection process 9 Specify the methods used to collect data from reports, including how many reviewers collected data from each report, whether they worked independently, any processes for obtaining or confirming data from study investigators, and if applicable, details of automation tools used in the process.

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Data items 10a List and define all outcomes for which data were sought.Specify whether all results that were compatible with each outcome domain in each study were sought (e.g. for all measures, time points, analyses), and if not, the methods used to decide which results to collect.

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10b List and define all other variables for which data were sought (e.g.participant and intervention characteristics, funding sources).Describe any assumptions made about any missing or unclear information.

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Study risk of bias assessment 11 Specify the methods used to assess risk of bias in the included studies, including details of the tool(s) used, how many reviewers assessed each study and whether they worked independently, and if applicable, details of automation tools used in the process.

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Effect measures 12 Specify for each outcome the effect measure(s) (e.g.risk ratio, mean difference) used in the synthesis or presentation of results.P5

Synthesis methods
13a Describe the processes used to decide which studies were eligible for each synthesis (e.g.tabulating the study intervention characteristics and comparing against the planned groups for each synthesis (item #5)).

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13b Describe any methods required to prepare the data for presentation or synthesis, such as handling of missing summary statistics, or data conversions.

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13c Describe any methods used to tabulate or visually display results of individual studies and syntheses.P5 13d Describe any methods used to synthesize results and provide a rationale for the choice(s).If meta-analysis was performed, describe the model(s), method(s) to identify the presence and extent of statistical heterogeneity, and software package(s) used.

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13e Describe any methods used to explore possible causes of heterogeneity among study results (e.g.subgroup analysis, meta-regression).P5 13f Describe any sensitivity analyses conducted to assess robustness of the synthesized results.P5

Reporting bias assessment
14 Describe any methods used to assess risk of bias due to missing results in a synthesis (arising from reporting biases).P5 Certainty assessment 15 Describe any methods used to assess certainty (or confidence) in the body of evidence for an outcome.P5

Study selection
16a Describe the results of the search and selection process, from the number of records identified in the search to the number of studies included in the review, ideally using a flow diagram.

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16b Cite studies that might appear to meet the inclusion criteria, but which were excluded, and explain why they were excluded.P5

Study characteristics
17 Cite each included study and present its characteristics.P5 Risk of bias in studies 18 Present assessments of risk of bias for each included study.P6

Results of individual studies
19 For all outcomes, present, for each study: (a) statistics for each group (where appropriate) and (b) an effect estimate and its precision (e.g.confidence/credible interval), ideally using structured tables or plots.

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Results of syntheses 20a For each synthesis, briefly summarise the characteristics and risk of bias among contributing studies.P6 20b Present results of all statistical syntheses conducted.If meta-analysis was done, present for each the summary estimate and its precision (e.g.confidence/credible interval) and measures of statistical heterogeneity.If comparing groups, describe the direction of the effect.

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20c Present results of all investigations of possible causes of heterogeneity among study results.P6 20d Present results of all sensitivity analyses conducted to assess the robustness of the synthesized results.P6 Reporting biases 21 Present assessments of risk of bias due to missing results (arising from reporting biases) for each synthesis assessed.P6

Certainty of evidence
22 Present assessments of certainty (or confidence) in the body of evidence for each outcome assessed.P6 For more information, visit: http://www.prisma-statement.org/

Supplementary Table 2. Quality assessment of studies included. Author, year Selection (Out of 4) Compa- rability (Out of 2) Outcomes (Out of 3) Total (Out of 9) Represent- ativeness of exposed cohort Selection of non-exposed cohort Ascer- tainment of expo- sure Outcome not present at the start of the study
Provide registration information for the review, including register name and registration number, or state that the review was not registered.inapplicable 24b Indicate where the review protocol can be accessed, or state that a protocol was not prepared.inapplicable 24c Describe and explain any amendments to information provided at registration or in the protocol.inapplicable Support 25 Describe sources of financial or non-financial support for the review, and the role of the funders or sponsors in the review.P2 Report which of the following are publicly available and where they can be found: template data collection forms; data extracted from included studies; data used for all analyses; analytic code; any other materials used in the review.